Clostridium difficile infections are a major healthcare burden. The incidence of C. difficile infections continues to rise and according to CDC estimates, approximately 500,000 people in U.S. are infected with C. difficile each year and C. difficile-associated diarrhea is the cause of 14,000 American deaths each year. Furthermore, the infections are no longer restricted to health care facilities, and recent studies indicate spred of C. difficile infection to the community as well. The annual burden of disease to the healthcare system due to C. difficile infections is estimated to be at least $1 billion. The current standard f care for C. difficile infections is stopping the offending antibiotic and use of different antibiotcs to target the bacterium. However, these are clearly inadequate since there is high mortality and high rates of recurrent infections, and thus we need to better understand the pathogenesis of C. difficile colitis to design newer therapeutic approaches. Our preliminary studies in patients with C. difficile infection and in a murine model of C. difficie colitis show that leptin signaling promotes an early inflammatory response that enhances disease but also clears pathogen. We now propose to identify the downstream mechanisms that are responsible for leptin actions, using a murine model of C. difficile colitis. We will use a mouse model of C. difficile colitis to determine the tempo and character of leptin-mediated inflammation and identify the critical mediators that are responsible for leptin- mediated disease enhancement and pathogen clearance. These studies will provide novel insights into the role of leptin in colonic inflammation and have the potential to uncover new therapeutic targets for possible host- directed treatments of C. difficile infections. This proposal leverages the institutional commitment and training environment at UVA, resources of the Petri Lab and inputs from expert collaborators and consultants in the fields of diarrheal disease research, C. difficile infections, gut microbiome studies, leptin biology and immunology. My career development plan includes structured oversight and guidance from my mentorship team, targeted coursework to acquire novel skills in key areas of the project (microbial pathogenesis, advanced immunology, biostatistics), focused workshops to enhance faculty development skills, publication benchmarks and plans to apply for independent funding, all of which will help establish me as an independent investigator in the field of C. difficile infections.